PROJECTSUMMARY Despitehalfacenturyofsocialandeconomicinvestments,anunprecedentedunderstandingofcancergenes andtheirpathways,andanarsenalofnewmolecularandimmunologicaltherapies,adiagnosisofmalignancy stillcarriessignificantmorbidityandmortality.Heraldedasabreakthroughforcancer?cures?,thepromiseof personalizedmedicine,whereeverypatientreceivestherightdrugfortherighttypeofcancerbasedon geneticmakeupisyettoberealized.Infact,mostmolecularly-targeteddrugshavebeendisappointinginthe clinic,producingonlyshort-livedresponses,oftenatstaggeringcostsandfinancialhardshipforthepatients, onlytobesupplantedbytheemergenceofdrug-resistantandmetastaticdisease.Weknowthatthe extraordinaryheterogeneityofhumantumors,withhundredsofmalignantclonesinconstantcompetitionand cooperationwitheachother,isamajorreasonfortreatmentfailure,butanin-depthunderstandingofthis processhasremainedsurprisinglyelusive.Workcarriedoutbyourgroupoverthepasttenyearshasfocused onmechanismsoftumoradaptation,orplasticityasnovel,fundamentaldriversofdiseaseheterogeneityand worsepatientoutcome.Wefoundthatstressconditionstypicalofthetumormicroenvironment,whether hypoxia,shortageofnutrients,proteintoxicityorexposuretomoleculartherapyactivateacoordinatedsetof cellularresponses,anetworkthatsustainscellproliferation,promotessurvival,reconfiguresmetabolism, stimulatesgeneexpression,andheightenscellmotilityandinvasion.Theneteffectforthemalignant populationisnotonlyimprovedfitnesstocopewithanunfavorablemicroenvironment,butalsotheacquisition ofnewtraitscharacteristicofaggressivedisease,includingdrug-resistanceandmetastaticcompetence. Unexpectedly,weidentifiedreprogrammingofmitochondrialfunctionsasanobligatoryhubforthisprocess, enablingorganelle-cytoskeletondynamics,assemblyofnovelapoptosis-regulatorycomplex(es),and retrogradegeneexpression.Therefore,thehypothesisthattumorplasticityimpartscellulardiversityin responsetostress,propagatestumorheterogeneityandpromotestheacquisitionofaggressivediseasetraits throughmitochondrialreprogrammingcanbeformulated,andwillconstitutethefocusofthepresent application.Theproposedstudieswilldissectthecellularandmolecularrequirementsoftumorplasticityasa novelhallmarkofcancer,credentialitsrelevanceinxenograftandgeneticmousemodelsoflocalizedand metastaticdisease,andexploitemergingvulnerabilitiesofthesepathwaysforinnovativecancerdrug discovery.Theresultswillestablishtumorplasticityasanoveldriverofdiseaseprogression,reacha comprehensiveblueprintoftheroleofmitochondrialhomeostasisincancer,andvalidatenew,actionable therapeutictargetsforpatientswithlate-stagedisease.